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標題: 天然植物化合物6-shogaol與pterostilbene抑制乳癌幹細胞特性及乳癌細胞侵入轉移之研究
Dietary agents 6-shogaol and pterostilbene as inhibitors of breast cancer stem cells and suppression of invasion and metastasis in breast cancer cells
作者: 洪伯翰
Hong, Bo-Han
關鍵字: Invadopodia,6-Shogaol;Invadopodia;Pterostilbene;Cancer stem cells;Mammospheres;6-Shogaol;Pterostilbene;腫瘤幹細胞;Mammospheres
出版社: 食品暨應用生物科技學系所
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乳癌位居世界癌症死因之第五位,具有高度轉移性、容易復發而難以根治,癌症轉移係指癌細胞為了得到更多養分,侵入到周遭組織中,甚至進入循環系統之過程。癌症之復發被認為與癌幹細胞 (cancer stem cells, CSCs)有關,一般而言,幹細胞 (stem cell)具有發展分化成許多不同細胞的能力,然而不正常的幹細胞則會成長為不正常的細胞群,像是乳癌幹細胞 (breast cancer stem cells, BCSCs)會生長擴張成具有抗藥性的細胞群,進一步限制目前癌症的治療功效。乳癌幹細胞可利用表面抗原CD44+/CD24-/low及其群聚成mammospheres之特性來做辨認。本研究目的為探討天然植物化合物是否能抑制乳癌細胞之侵入與移行,以及其對於MCF7分離之乳癌幹細胞是否具有抑制活性與未來可否能輔助化學治療以根治乳癌。植物化合物(phytochemicals)對人體有許多益處且相較於藥物較無副作用,同時近年來其抗癌活性亦被廣泛探討。故本研究首先評估兩種天然植物化合物,6-shogaol(6-S)與pterostilbene(Pet)對乳癌細胞株MDA-MB231及T47D細胞之matrix metalloproteinase(MMPs)活性、細胞移行與侵入試驗。結果發現6-S與Pet分別於10及25uM濃度即能有效抑制MDA-MB231及T47D細胞之MMP-2與MMP-9活性、顯著降低其細胞侵入與移行現象。Invadopodia是在侵入性癌細胞中特有的一種細胞結構,為癌細胞侵入過程中降解基質的主要角色,其組成之核心蛋白包含cortactin與MT1-MMP。進一步分析Invadopodia核心蛋白cortactin與MT1-MMP蛋白質表現。實驗結果顯示,6-S及Pet 於2小時抑制MDA-MB231細胞cortactin與MT1-MMP之蛋白表現。
本研究進一步以五種天然植物化合物: 6-gingerol (6-G)、6-S、5-hydroxy-3,6,7,8,3‘,4‘-hexamethoxyflavone (5-Hs)、nobiletin (Nol)和Pet分別測定乳癌細胞株MCF7及其分離之乳癌幹細胞 (BCSCs)之細胞存活率,結果顯示,在處理劑量25與50uM時,6-S及Pet能專一性毒殺乳癌幹細胞,同時對於MCF7較不具毒性。以6-S和Pet分別測定其對於mammospheres以及結合化療藥物paclitaxel對乳癌幹細胞分化群之存活率影響。結果顯示6-S及Pet 和乳癌幹細胞共培養72小時,可顯著抑制mammospheres形成,且具有輔助低劑量臨床化療藥物paclitaxel降低乳癌幹細胞分化群存活之效用。因此,6-S及Pet能減少乳癌幹細胞群存活、mammospheres群聚數與體積以及輔助化療藥物之功效。許多訊息調控路徑像是hedgehog、PI3K/Akt和Wnt/b-catenin與細胞自我更新、正常器官幹細胞或胚胎幹細胞存活相關。而最近文獻中也指出,這些訊息路徑也可能參與維持CD44+/CD24-/low乳癌幹細胞之stemness特性。進一步探討化合物之作用機制是否可以調控這些訊息傳遞路徑,結果發現6-S與Pet皆能於72小時有效降低細胞表面抗原CD44表現量。其中6-S和Pet可提升b-catenin降解活性,而減少下游c-Myc、cyclinD1蛋白質表現,其主要是透過抑制hedgehog蛋白質表現、Akt及GSK3B之磷酸化,而降低b-catenin轉錄程度。由以上結果得知,6-S與Pet能抑制乳癌細胞侵入移行之程度並且透過調節b-catenin磷酸化表現而降低CD44表現,而抑制mammospheres生成,影響乳癌幹細胞特性之維持。
綜合上述,6-S和Pet不僅具有降低癌細胞轉移之抗癌能力,同時也能作用於抑制其幹細胞特性,因此推測6-S及Pet 可能有潛力作為化療藥物之佐劑。

Breast cancer, the fifth leading cause of malignancy-related death in the world, is hard to eradicate because of the highly metastasis and easily relapse. Tumor metastases are defined as the invasion of cancer cells into their surrounding tissues, or even to the circulatory system, when the cells lack nutrients. The relapses of cancer are typically considered to be related to cancer stem cells (CSCs). Stem cells have the ability to differentiate into different types of cells. Consequently, abnormal stem cells can develop into a group of abnormal cells. For instance, breast cancer stem cells can grow and develop into therapy-resistant colonies and therefore limit the efficiency of the modern chemotherapy. Breast cancer stem cells (BCSCs) could be identified by special cell surface markers CD44+/CD24-/low and nonadherent spherical cell clusters termed mammospheres. Recently, phytochemicals have been widely discussed for their chemopreventive activities because they offered the similar benefits but with less toxicity than the clinical chemotherapy. The aim of this study was to determine the anti-metastasis effects of phytochemicals on two different breast cancer cell lines, MDA-MB231 and T47D, and the potential anti-cancer effect on target BCSCs, isolated from the breast cancer MCF7 cell line. 6-Shogaol (6-S) and pterostilbene (Pet), two nature compounds, were used to investigate their inhibitory effects on cancer invasion and migration. 6-S and Pet were found to have the ability to inhibit MMP-2/9 activities, cell migration and invasion of MDA-MB231 cells for 24 h at 25 uM and 50 uM. Invadopodia, special structures mainly consist of core protein cortactin and MT1-MMP on cancer cell membranes, are found to assist malignant cancer cells in their invasion and migration into other tissues. This study also indicated that 6-S and Pet significantly reduced the protein expressions of cortactin and MT1-MMP in MDA-MB231 cells for 2 h at 10 uM and 25uM.
Five phytochemicals, including 6-gingerol (6-G), 6-S, 5-hydroxy-3,6,7,8,3‘,4‘-hexamethoxyflavone (5-Hs), nobiletin (Nol) and Pet were used to investigate their effects on cell viabilities of MCF7 cells and BCSCs. The results showed that 6-S and Pet were able to selectively kill BCSCs but not MCF7 cells at 25 and 50 uM. These two effective compounds, 6-S and Pet were then used to investigate their effects on mammospheres formations in BCSCs. The results showed that 6-S and Pet inhibited the formation of mammospheres after co-incubation with BCSCs for 72 h, respectively. Furthermore, 6-S and Pet were applied to evaluate cell viabilities when combined with paclitaxel in differentiated BCSCs. Our results showed that both 6-S and Pet assisted paclitaxel to reduce cell viability in differentiated BCSCs. Therefore, treatments with 6-S and Pet could reduce cell viability and mammospheres formations in BCSCs and assist chemotherapy to inhibit cell survival in differentiated BCSCs. In the previous studies, many signaling transductions like hedgehog, Notch, PI3K/Akt and Wnt/b-catenin were found to be highly related to the survival and self-renewal of stem cells. Moreover, the recent researches showed these signaling molecules are also involved in the CD44 expression and the stemness maintenance of cancer stem cells. 6-S and Pet effectively reduced the CD44 expression in the BCSCs after 72 h co-incubation. Immunoblotting analysis showed that 6-S and Pet inhibited cyclinD1, c-Myc and GSK3B phosphorylation, but increased b-catenin phosphorylation through inhibiting hedgehog and Akt phosphorylation in the BCSCs.
These data suggest that 6-S and Pet work not only by reducing cell metastasis but also by inhibiting stemness of the malignant cancer stem cells. In conclusion, 6-S and Pet may have the potential to be adjuvants of chemotherapy.
其他識別: U0005-1808201110041900
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